Small cell lung cancer (SCLC), which comprises about 15% of all lung cancers, was designated as a recalcitrant cancer by NCI in 2014. Novel therapy against SCLC is urgently needed. In a high-throughput screen, BET bromodomain inhibitors (BETi) were identified as a promising class of drugs against SCLC. BETi decreases transcriptional activity of BET family proteins (BRD2, BRD3, BRD4 and BRDT) by blocking binding of these proteins to active chromatin. In phase I trials, BETi showed promising activity in hematological malignancies as well as in NUT-midline carcinomas. Preclinical studies done in my labs and other groups have suggested two challenges in applying BETi for SCLC treatment. First, it was found that only 50-60% of SCLC cell lines are sensitive to BETi. Secondly, my lab found that, in sensitive SCLC cells, BETi treatment caused G1 cell cycle arrest and apoptosis was only evident at relatively high doses. To enhance the effect of BETi, we did a high-throughput matrix combination screen and found a number of inhibitors synergized with BETis. These findings were confirmed independently. We focused on one drug combination for further study. The selected combination was found to cause more apoptosis and was also synergistic in inhibiting cell growth in SCLC cell lines that were initially resistant to BETi. We are currently in the process to uncover the signaling pathways that are impacted on by the drug combo. In addition, we have also in the process to initiate a phase I/II clinical trial to explore therapeutic potentials of this drug combo in SCLC.